During the course of our studies of HIV-2 viral protein X (Vpx), we made the serendipitous discovery of Vpx interaction with invariant chain (li), and loss of li expression in Vpx transfected and HIV-2 infected cells. Therefore, the proposed studies will investigate the importance of this observation with regards to understanding the pathogenesis of HIV-2 and SIVmac. 1. Interaction of Vpx with invariant chain - We have found that Vpx interacts with human invariant chain (li), resulting in depletion of li from antigen-presenting cells. The proposed studies will further define the significance of this observation by further definition of the interacting sequences and examining the effects of Vpx on antigen presentation to CD4+ T cells. 2. Significance of Vpx activities in vivo Vpx has been shown to be critical for SlVmac to establish infection after intravaginal exposure. It is unclear whether this is due to interaction of Vpx with li and defective CD4+ helper T cell responses, defective Vpx-mediated nuclear import of the preintegration complex of quiescent cells, or both of these properties of Vpx, or neither property. We will map the domains of SIVmac Vpx that are critical for nuclear localization and li interaction. Mutant SIVmac Vpx selectively missing each activity will then be studied by infection of rhesus macaques.